CN107235992A - Indolone spiral shell thiophane class compound and its salt, preparation method and application - Google Patents
Indolone spiral shell thiophane class compound and its salt, preparation method and application Download PDFInfo
- Publication number
- CN107235992A CN107235992A CN201710548337.XA CN201710548337A CN107235992A CN 107235992 A CN107235992 A CN 107235992A CN 201710548337 A CN201710548337 A CN 201710548337A CN 107235992 A CN107235992 A CN 107235992A
- Authority
- CN
- China
- Prior art keywords
- compound
- low
- thiophane
- spiral shell
- enantiomter
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- GKIMVZDPIWPNIU-UHFFFAOYSA-N CC(C)(C)c1ccc2OCOc2c1 Chemical compound CC(C)(C)c1ccc2OCOc2c1 GKIMVZDPIWPNIU-UHFFFAOYSA-N 0.000 description 1
- KQYWTUZIDAOJEM-VPEKBSMISA-N CC([C@@H](c1ccccc1)NC(N[C@@H](CCCC1)[C@H]1N(C)C)=S)c1ccccc1 Chemical compound CC([C@@H](c1ccccc1)NC(N[C@@H](CCCC1)[C@H]1N(C)C)=S)c1ccccc1 KQYWTUZIDAOJEM-VPEKBSMISA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/10—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of indolone spiral shell thiophane class compound and its salt, preparation method and application, belongs to pharmaceutical technology field.The indolone spiral shell thiophane class compound that the present invention is provided has brand-new skeleton structure and stronger antitumor activity, more obvious inhibited proliferation is generated to human lung carcinoma cell, human breast cancer cell and intestinal cancer HCT116, the antitumor activity of part of compounds is better than positive control drug Nutlin 3, can be applied in antineoplastic is prepared.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to indolone spiral shell thiophane class compound and its salt, preparation side
Method and application.
Background technology
Spiral shell indolone skeleton receives organic synthesis and pharmaceutical chemistry as natural products and the advantage skeleton of bioactive molecule
The extensive concern of researcher.At present, it has been reported that multifarious spiral shell indole ketone compound, and find have extensive medicine
Reason activity, such as progestogen receptor regulator (Jay E.Wrobel et al, Design, Synthesis, and SAR of New
Pyrrole-Oxindole Progesterone Receptor Modulators Leading to 5-(7-Fluoro-3,3-
dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -1-methyl-1H-pyrrole-2-carbonitrile
(WAY-255348),J.Med.Chem.2008,51:1861-1873), anti-AIDS (Singh RK.et al, Rhodium
(II)acetate-catalyzed stereoselective synthesis,SAR and anti-HIV activity of
novel oxindoles bearing cyclopropane ring,Eur.J.Med.Chem.2011,46:1181-1188)、
Antitumor (WO20080 55812A1), antituberculosis (Waldmann, H.et al, Identification of
thiazolidinones spiro-fused to indolin-2-ones as potent and selective
inhibitors of the Mycobacterium tuberculosis protein tyrosine phosphatase B,
Angew.Chem.Int.Ed. Engl.2010,49:5902-5905), anti-malarial (Diagana, T.T.et al,
Spiroindolones,a potent compound class for the treatment of malaria,Science
2010,329:1175-1180) with MDM2 inhibitor (Wang, S.et al, Structure-based design of
potent non-peptide MDM2 inhibitors,J.Am.Chem.Soc.2005,127:10130-10131) etc..
Inventor constructs two class new indole ketone spiral shell tetrahydrochysene thio-pyrylium analog derivatives, and find in previous work
It has good anti tumor activity in vitro (publication No.：CN103992334A、CN106565742A).On this Research foundation,
In order to further do the research deeper entered to indolone spiral shell tetrahydrochysene thio-pyrylium analog derivative and find preferably antitumorization
Compound, inventor further constructs a class new indole ketone spiral shell thiophane class compound.
The content of the invention
It is an object of the invention to provide a kind of indolone spiral shell thiophane class compound and its salt, preparation method and should
With.Such compound has brand-new skeleton structure and stronger antitumor activity, can be applied in antineoplastic is prepared.
The present invention is to be achieved through the following technical solutions：
A kind of indolone spiral shell thiophane class compound, including its raceme, d- types or l- type isomers, wherein, the change
The structure of compound is as shown in formula I：
Wherein R1The substituent on phenyl ring is represented, the wherein substituent on phenyl ring is monosubstituted or polysubstituted, replaces base table
Show hydrogen, halogen, low-grade halogenated alkyl, low alkyl group, hydroxyl, Lower hydroxy alkyl, lower alkoxy, amino, lower alkyl-ammonium
It is base, low-grade halogenated alkyl amino, low-grade cycloalkyl amino, alkynyl of low-grade chain amino, nitro, rudimentary 4-nitro alkyl, cyano group, rudimentary
Cyanoalkyl, amide groups, low-grade cycloalkyl amide groups, rudimentary amido alkyl；
R2Aromatic ring substituents group is represented, the aromatic ring is phenyl ring, substituted benzene ring or hetero-aromatic ring；Taking on the substituted benzene ring
Dai Jiwei halogens, low alkyl group, hydroxyl, lower alkoxy, amino, low-grade alkyl amino, low-grade cycloalkyl amino, nitro, acyl
Amido or low-grade cycloalkyl amide groups；The hetero-aromatic ring is pyrroles, furans, thiophene or pyridine；
R3Represent hydrogen, low alkyl group or lower Oxo side chain；
R4Aromatic ring substituents group is represented, the aromatic ring is phenyl ring, substituted benzene ring or hetero-aromatic ring；Substitution on substituted benzene ring
Base is halogen, low alkyl group, hydroxyl, lower alkoxy, amino, low-grade alkyl amino, low-grade cycloalkyl amino, nitro, acid amides
Base or low-grade cycloalkyl amide groups；The hetero-aromatic ring is furans, thiophene, pyrroles or pyridine；
Described " low-grade cycloalkyl " refers to the ring containing 3 to 7 carbon, and described " alkynyl of low-grade chain amino " refers to accordingly
The amount of carbon atom of alkynes chain is 3 to 6, and other described " rudimentary " substituents refer to that corresponding aliphatic group is straight or branched
, saturation and containing 1 to 6 carbon atom.
Preferably, in R1In the substituent of expression, the halogen is fluorine, chlorine or bromine, and the low alkyl group is methyl；In R2
In the aromatic ring substituents group of expression, substituted benzene ring substituted radical is 4- bromophenyls or 3,4- dichlorophenyl.
Preferably, in R4Substituted benzene ring substituted radical is in the aromatic ring substituents group of expression：4- bromophenyls, 3- bromophenyls,
2- fluorophenyls, 4- aminomethyl phenyls, 4- methoxyphenyls, 2,4 difluorobenzene base orIn R4The aromatic ring substitution of expression
Heteroaromatic substituted radical is in group：
Preferably, the R of the compound1、R2、R3、R4One kind in following combination：
。
A kind of preparation method of indolone spiral shell thiophane class compound, its reaction equation is as follows：
Wherein, compound of formula VI, Formula VII compound and catalyst VIII are added in solvent, at 20~30 DEG C
10~14h is stirred, after reaction completely, 10~20min of reaction at pyridine, thionyl chloride, 20~30 DEG C is continuously added, separates pure
Change, obtain target product I；
Wherein, catalyst VIII is thiosemicarbazide bifunctional catalyst.
Preferably, according to molar amount, catalyst VIII consumption is the 5~15% of compound of formula VI.
Preferably, the solvent is dichloromethane.Preferably, catalyst VIII is one kind in A1~A9, compound A1
The racemic modification of any enantiomter or a kind of and its enantiomter composition in compound A1~A9 in~A9；
Compound A1~A9 structure is as follows：
It is further preferred that
When target product I structure is I A：
Catalyst VIII is A3, A6, A9, A1 enantiomter, A4 enantiomter, A5 enantiomter, A7
Enantiomter or A8 enantiomter；
When target product I structure is I B：
Catalyst VIII is different for the mapping of A1, A4, A5, A7, A8, A3 enantiomter, A6 enantiomter or A9
Structure body；
When target product I is racemic modification, catalyst VIII is a kind of and its enantiomerism in compound A1~A9
The racemic modification of body composition.
It is further preferred that the preparation method of compound of formula VI is as follows：
Wherein, R is worked as3During for hydrogen, compounds of formula V is compound of formula VI.
Concretely comprise the following steps：
A) preparation of intermediate II：Nitromethane, the benzaldehyde of substitution and ammonium acetate are added in acetic acid, and 90~
Reacted at 110 DEG C, after reaction completely, isolate and purify, obtain intermediate II；
B) preparation of intermediate III：In dichloromethane, addition intermediate II, chloroacetic chloride and anhydrous ferric trichloride, 20~
Reacted at 30 DEG C, after reaction completely, isolate and purify, obtain intermediate III；
C) intermediate V preparation：Under nitrogen protection, intermediate III, intermediate compound IV, triethylamine are added to dichloromethane
In alkane, and the stirring reaction at 20~30 DEG C, after reaction completely, isolate and purify, obtain intermediate V；
D) intermediate VI preparation：In dichloromethane, compound V, substitution reagent and 4- dimethylamino pyridines are added, instead
After answering completely, isolate and purify, obtain intermediate VI；Wherein, the substitution reagent is acid anhydrides or brominated alkanes.
Present invention also offers the officinal salt of described indolone spiral shell thiophane class compound.
Present invention also offers described indolone spiral shell thiophane class compound or pharmaceutically acceptable salt thereof prepare it is antitumor
Application in medicine.
Preferably, described tumour is lung cancer, intestinal cancer, breast cancer or liver cancer.
Compared with prior art, the present invention, which is provided, has following beneficial effect：
The indolone spiral shell thiophane class compound that the present invention is provided, to A549 (human lung carcinoma cell), MCF-7 (people's mammary gland
Cancer cell) and intestinal cancer HCT116 generate more obvious inhibited proliferation, it has novel structure and preferably anti-
Tumor promotion, can be applied in the preparation of antineoplastic.
The synthetic method that the present invention is provided, synthetic route is simple, and synthesis material is easy to get, synthetic method is easily realized.
The indolone spiral shell thiophane class compound or pharmaceutically acceptable salt thereof that the present invention is provided is in anti-cancer drug preparation is prepared
Application, more selections can be provided for clinical treatment.
Brief description of the drawings
Fig. 1：For compound 1A X single crystal diffraction data.
The ee that Fig. 2 is raceme compound 1C prepared by embodiment 19 determines analysis chart.
Compound 1As of the Fig. 3 to be prepared in embodiment 1 ee determines analysis chart, wherein, measurement result is shown, its ee value is
90%.
Embodiment
In conjunction with embodiment and accompanying drawing, the present invention is described in detail, but the implementation of the present invention is not limited only to this.The present invention
Agents useful for same and raw material are commercially available or can be prepared by literature method.
The experimental method of unreceipted actual conditions in the following example, generally according to normal condition, or according to manufacturer
Proposed condition.
The chemical structural formula of the corresponding formula I of compound involved by following examples,1H-NMR、13C-NMR, HRMS and HPLC number
According to referring to table 2.
The part preferred compound of the present invention of table 21H-NMR,13C-NMR, HRMS and HPLC data
Embodiment 1：Compound 1A synthesis
The preparation (intermediate II) of A intermediates (E) -1- bromo- 2- (2- nitroethenyl groups) benzene
Method (the Advanced Synthesis＆Catalysis 2013,355 of reference literature report:829-835).Will
Nitromethane (7.2mL, 0.134mol), 2- bromobenzaldehydes (4.0g, 0.022mol) and ammonium acetate (0.20g, 2.6mmol) add
Enter into 80mL acetic acid, and 10h is reacted at 100 DEG C.After reaction completely, solvent evaporated, residue column chromatography purifying (oil
Ether：Ethyl acetate=100:3) (E) -1- bromo- 2- (2- nitroethenyl groups) benzene, is obtained for yellow solid 4.21g, and yield is
85.4%.
The preparation (intermediate III) of the bromo- 3- chloro-indoles -2- ketone of B intermediates 4-
Method (the Advanced Synthesis＆Catalysis 2013,355 of reference literature report:829-835).
In 50mL dichloromethane, add (E) -1- bromo- 2- (2- nitroethenyl groups) benzene (3.2g, 14.0mmol), chloroacetic chloride (2.1mL,
29.6mmol) with anhydrous ferric trichloride (4.64g, 28.6mmol), 3 h are reacted at room temperature.After reaction completely, solvent evaporated is residual
Thing column chromatography is stayed to purify (DCM:MeOH=100:1) the bromo- 3- chloro-indoles -2- ketone of 4-, is obtained for white-yellowish solid 2.25g, yield
For 65.6%.
The preparation (intermediate V) of the bromo- 3- of C intermediates 4- ((2- oxo -2- phenethyls) sulphur) indol-2-one
In 20mL dichloromethane, the bromo- 3- chloro-indoles -2- ketone (0.3g, 1.22mmol) of 4-, 2- sulfydryl -1- benzene are added
The triethylamine of ethyl ketone (0.24g, 1.59mmol) and 0.1mL, the lower room temperature reaction of nitrogen protection is stayed overnight.After reaction completely, it is evaporated molten
Agent, residue column chromatography purifying (DCM:MeOH=100:1) intermediate V, is obtained for white-yellowish solid 0.27g, and yield is 62%
。1H NMR(400MHz,CDCl3) δ 4.11 (d, J=15.5Hz, 1H), 4.34 (d, J=15.5Hz, 1H), 4.48 (s, 1H),
6.82 (d, J=7.4 Hz, 1H), 7.10-7.17 (m, 2H), 7.46 (t, J=7.7Hz, 2H), 7.59 (t, J=7.4Hz, 1H),
7.93 (d, J=8.0Hz, 2H), 8.37 (s, 1H)13C NMR(100MHz,CDCl3)δ36.13,45.49, 108.95,
120.63,124.97,126.57,128.60(2C),128.68(2C),130.84,133.52,135.55, 142.76,
175.76,194.37.HRMS(ESI+)m/z calculated for C16H13BrNO2S(M+H): 361.9850,found
361.9848.
D target compounds 1A preparation
In 2mL DCM, catalyst (CAS is sequentially added:1448608-06-7,0.01mmol), intermediate V
(0.10mmol) and VII (0.12mmol), at room temperature stirring reaction 12h.Reaction completely after, sequentially add pyridine (2mmol) and
Thionyl chloride (1mmol), at room temperature stirring reaction 15min.After reaction completely, solvent evaporated.Residue is purified through column chromatography
(DCM) target compound 1A-- (2'R, 3'R, 4'R, 5'S)-type target compound is obtained, is white solid (38mg), yield
It is 90% for 72%, ee values.
Wherein, the condition that uses is the HPLC (μ of Chiralpak OD, 0.46cm I.D. × 25cm L × 5 when determining ee values
M, 25 DEG C, isopropanol/n-hexane=15:85, flow velocity 0.8mL/min, λ=254nm).
Embodiment 2：The synthesis of compound 2
With reference to embodiment 1.The bromo- 3- of intermediate 4- ((2- oxo -2- phenethyls) sulphur) indol-2-ones (0.10mmol) with
The bromo- beta-nitrostyrenes of 4- (0.12mmol) react, and prepare compound 2 is white solid (42mg), yield 69%, and ee values are
93%.
Embodiment 3：The synthesis of compound 3
With reference to embodiment 1.The bromo- 3- of intermediate 4- ((2- oxo -2- phenethyls) sulphur) indol-2-ones (0.10mmol) with
The fluoro- beta-nitrostyrenes of 2- (0.12mmol) react, and prepare compound 3 is white solid (34mg), yield 62%, and ee values are
93%.
Embodiment 4：The synthesis of compound 4
With reference to embodiment 1.The bromo- 3- of intermediate 4- ((2- oxo -2- phenethyls) sulphur) indol-2-ones (0.10mmol) with
The bromo- beta-nitrostyrenes of 3- (0.12mmol) react, and obtain compound 4 for white solid (42mg), yield 69%, and ee values are
92%.
Embodiment 5：The synthesis of compound 5
With reference to embodiment 1.The bromo- 3- of intermediate 4- ((2- oxo -2- phenethyls) sulphur) indol-2-ones (0.10mmol) with
4- methyl-nitrostyrenes (0.12mmol) react, and obtain compound 5 for white solid (35mg), yield 65%, and ee values are
91%.
Embodiment 6：The synthesis of compound 6
With reference to embodiment 1.The bromo- 3- of intermediate 4- ((2- oxo -2- phenethyls) sulphur) indol-2-ones (0.10mmol) with
4- methoxyl groups-beta-nitrostyrene (0.12mmol) reaction, prepare compound 6 is white solid (42 mg), yield 75%, ee
It is worth for 93%.
Embodiment 7：The synthesis of compound 7
With reference to embodiment 1.The bromo- 3- of intermediate 4- ((2- oxo -2- phenethyls) sulphur) indol-2-ones (0.10mmol) with
3,5- bis- fluoro- beta-nitrostyrene (0.12mmol) reactions, prepare compound 7 is white solid (39mg), yield 69%, ee values
For 85%.
Embodiment 8：The synthesis of compound 8
With reference to embodiment 1.The bromo- 3- of intermediate 4- ((2- (4- bromophenyls) -2- oxoethyls) sulphur) indol-2-one
(0.10mmol) and beta-nitrostyrene (0.12mmol) react, and prepare compound 8 is white solid (39 mg), yield 64%,
Ee values are 90%.
Embodiment 9：The synthesis of compound 9
With reference to embodiment 1.The chloro- 3- of intermediate 4- ((2- (3,4- dichlorophenyls) -2- oxoethyls) sulphur) indol-2-one
(0.10mmol) and beta-nitrostyrene (0.12mmol) react, and prepare compound 9 is white solid (39 mg), yield 71%,
Ee values are 87%.
Embodiment 10：The synthesis of compound 10
With reference to embodiment 1.The chloro- 3- of intermediate 4- ((2- oxo -2- phenethyls) sulphur) indol-2-ones (0.10mmol) with
Beta-nitrostyrene (0.12mmol) reacts, and prepare compound 10 is white solid (33mg), yield 68%, ee values 92%.
Embodiment 11：The synthesis of compound 11
With reference to embodiment 1.The fluoro- 3- of intermediate 5- ((2- oxo -2- phenethyls) sulphur) indol-2-ones (0.10mmol) with
Beta-nitrostyrene (0.12mmol) reacts, and obtains compound 11 for white solid (33mg), yield 71%, ee values 87%.
Embodiment 12：The synthesis of compound 12
With reference to embodiment 1.Intermediate 6- methyl -3- ((2- oxo -2- phenethyls) sulphur) indol-2-one (0.10mmol)
Reacted with beta-nitrostyrene (0.12mmol), obtain compound 12 for white solid (25mg), yield 54%, ee values 91%.
Embodiment 13：The synthesis of compound 13
With reference to embodiment 1.Intermediate 3- ((2- oxo -2- phenethyls) sulphur) indol-2-ones (0.10mmol) and β-nitro
Styrene (0.12mmol) reacts, and prepare compound 13 is white solid (29mg), yield 64%, ee values 91%.
Embodiment 14：The synthesis of compound 14
With reference to embodiment 1.The bromo- 3- of intermediate 4- ((2- oxo -2- phenethyls) sulphur) indol-2-ones (0.10mmol) with
(E) -2- (2- nitroethenyl groups) furans (0.12mmol) reacts, and obtains compound 14 for white solid (30 mg), yield
58%, ee value 91%.
Embodiment 15：The synthesis of compound 15
With reference to embodiment 1.The bromo- 3- of intermediate 4- ((2- oxo -2- phenethyls) sulphur) indol-2-ones (0.10mmol) with
(E) -1- ethyls -2- (2- nitroethenyl groups) -1H- indoles (0.12mmol) reacts, and obtains compound 15 for white solid
(45mg), yield 76%, ee values 80%.
Embodiment 16：The synthesis of compound 16
With reference to embodiment 1.Intermediate 3- ((2- oxo -2- phenethyls) sulphur) indol-2-one (0.10mmol)
(0.10mmol) reacts with (E) -5- (2- nitroethenyl groups) benzo [d] [1,3] dioxole (0.12mmol), is changed
Compound 16 is white solid (38mg), yield 77%, ee values 87%.
Embodiment 17：The synthesis of compound 17
With reference to embodiment 1.The bromo- 3- of intermediate 4- ((2- oxo -2- phenethyls) sulphur) indol-2-one (0.10mmol)
(0.10mmol) reacts with (E) -5- (2- nitroethenyl groups) benzo [d] [1,3] dioxole (0.12mmol), is changed
Compound 17 is faint yellow solid (45mg), yield 79%, ee values 86%.
Embodiment 18：The synthesis of compound 18
With reference to embodiment 1.The chloro- 3- of intermediate 1- acetyl group -4- ((2- oxo -2- phenethyls) sulphur) indol-2-one
(0.10mmol) reacts with (E) -5- (2- nitroethenyl groups) benzo [d] [1,3] dioxole (0.12mmol), is changed
Compound 18 is faint yellow solid (42mg), yield 74%, ee values 68%.
Embodiment 19：Compound 1A raceme 1C preparation
In 2mL DCM, racemization body catalyst VIII (CAS are sequentially added:1448608-06-7 and CAS:1448608-
Two kinds of 07-8 correspondence isomers mixed in equal amounts, 0.01mmol), intermediate V (0.10 mmol) and VII (0.12mmol), at room temperature
Stirring reaction 12h.After reaction completely, pyridine (2mmol) and thionyl chloride (1mmol) are sequentially added, at room temperature stirring reaction
15min.After reaction completely, solvent evaporated.Residue purifies (DCM) through column chromatography and obtains target compound 1C, is white solid
(38 mg), yield is 72%.Gained raceme 1C determines its ee value by HPLC, and test result shows that in figure 3, display should
Raceme 1C ee values only have 17%.
The preparation of other raceme target compounds is with reference to embodiment 19.
Embodiment 20：The enantiomter 1B of compound 1 preparation
In 2mL DCM, catalyst VIII enantiomter (CAS is sequentially added:1448608-07-8,
0.01mmol), intermediate V (0.10mmol) and VII (0.12mmol), at room temperature stirring reaction 12h.After reaction completely, successively
Pyridine (2mmol) and thionyl chloride (1 mmol) are added, at room temperature stirring reaction 15min.After reaction completely, solvent evaporated.It is residual
Stay thing to purify (DCM) through column chromatography and obtain target compound 1B-- (2'S, 3'S, 4'S, 5'R), be white solid (38mg), receive
Rate is 72%.
The preparation of other enantiomters is with reference to embodiment 20.
Embodiment 21：The chiral influence of different catalysts
In order to inquire into the influence that different catalysts are chiral to product, the present embodiment to catalyst A1, A2, A3, A5, A6,
A8, A9, A10, A11 are tested, and the reaction equation of test is as follows：
In 2mL solvent, catalyst, intermediate V (0.10mmol) and VII (0.12 mmol) are sequentially added, at room temperature
Stirring reaction.After reaction completely, pyridine (2mmol) and thionyl chloride (1mmol) are sequentially added, at room temperature stirring reaction
15min.After reaction completely, solvent evaporated.Residue purifies (DCM) through column chromatography and obtains target compound 1A.
Acquired results are illustrated in table 3.Wherein, in table 3, unless made mark, otherwise catalyst amount is intermediate V
The 10% of mole.
Table 3：Using different catalysts prepare compound 1A ee value results
Wherein, dr is to pass through1What H NMR were determined, ee is determined by HPLC.
Wherein, the structure of the catalyst used for：
Embodiment 22：The anti-tumor activity test of the compounds of this invention
Selected part compound has carried out Cytostatic to tumor cell experiment, and test method uses conventional MTT methods (such as
Lv Qiujun is edited《Developmental pharmacology research method》, 2007：242-243).
Cell line selects lung cancer A549, breast cancer MCF-7 and intestinal cancer HCT116, is purchased from Shanghai City medical industry research
Institute.
Nutrient solution is that DMEM+15%NBS+ is dual anti-.
Sample liquid is prepared：After being dissolved with DMSO (Merck), the solution or uniform mixed that PBS (-) is made into 100 μ g/mL is added
Suspension, then with DMSO PBS (-) dilution, ultimate density be respectively 10 μ g/mL, 1 μ g/mL, 0.1 μ g/mL, 0.01 μ g/mL,
0.001μg/mL、0.0001μg/mL。
Antitumoral compounds Nutlin-3 is made into reference substance solution with same condition.
It is 3 × 10 that 96 orifice plates, which add concentration per hole,4Individual/mL μ the L of cell suspension 100, i.e., 3000 cells/wells put 37
DEG C, 5%CO2In incubator.After 24 hours, sample liquid and reference substance liquid are separately added into, 10 μ L/ holes, 37 DEG C act on 72 hours.
The 5mg/mL μ L of MTT (3- (4,5- dimethylthiazole -2- bases) -2,5- diphenyltetrazoliumbromide father-in-law bromide) solution 20 are added per hole,
Effect adds lysate DMSO after 4 hours, and 100 μ L/ holes are put in incubator, and the secondary daily full-automatic ELIASAs of MK-2 survey 570nm
OD values, calculation of half inhibitory concentration IC50。
The antitumor activity of part of compounds refers to table 4.As a result show, this kind of compound aggregate performance goes out wide spectrum, stronger
Antitumor activity, hence it is evident that better than positive control Nutlin-3 (CAS:548472-68-0), it can be tied as antineoplastic guide
Structure carries out more in-depth study.In addition, the compound of present patent application contains the base that nitro, chlorine, amino etc. are easy to derivatization
Group, is easy to quick derivatization, finds the antitumor lead compound of good activity.
Half-inhibition concentration IC of the part of compounds of table 4 to tumour cell50(unit：μM)
Above test result indicates that, compound of the invention has good antitumor activity, therefore the compounds of this invention
It can be used for preparing antineoplastic.
The preferred embodiment to the invention is illustrated above, but the invention be not limited to it is described
Embodiment, those skilled in the art can also make a variety of equivalent on the premise of without prejudice to the invention spirit
Modification or replacement, these equivalent modifications or replacement are all contained in the application claim limited range.
Claims (10)
1. a kind of indolone spiral shell thiophane class compound, including its raceme, d- types or l- type isomers, it is characterised in that
The structure of the compound is as shown in formula I：
Wherein R1Represent the substituent on phenyl ring, wherein the substituent on phenyl ring be it is monosubstituted or polysubstituted, substitution basis representation hydrogen,
It is halogen, low-grade halogenated alkyl, low alkyl group, hydroxyl, Lower hydroxy alkyl, lower alkoxy, amino, low-grade alkyl amino, low
Level haloalkylamino, low-grade cycloalkyl amino, alkynyl of low-grade chain amino, nitro, rudimentary 4-nitro alkyl, cyano group, rudimentary cyano group
Alkyl, amide groups, low-grade cycloalkyl amide groups, rudimentary amido alkyl；
R2Aromatic ring substituents group is represented, the aromatic ring is phenyl ring, substituted benzene ring or hetero-aromatic ring；Substituent on the substituted benzene ring
For halogen, low alkyl group, hydroxyl, lower alkoxy, amino, low-grade alkyl amino, low-grade cycloalkyl amino, nitro, amide groups
Or low-grade cycloalkyl amide groups；The hetero-aromatic ring is pyrroles, furans, thiophene or pyridine；
R3Represent hydrogen, low alkyl group or lower Oxo side chain；
R4Aromatic ring substituents group is represented, the aromatic ring is phenyl ring, substituted benzene ring or hetero-aromatic ring；Substituent on substituted benzene ring is
Halogen, low alkyl group, hydroxyl, lower alkoxy, amino, low-grade alkyl amino, low-grade cycloalkyl amino, nitro, amide groups or
Low-grade cycloalkyl amide groups；The hetero-aromatic ring is furans, thiophene, pyrroles or pyridine；
Described " low-grade cycloalkyl " refers to the ring containing 3 to 7 carbon, and described " alkynyl of low-grade chain amino " refers to corresponding alkynes chain
Amount of carbon atom be 3 to 6, other described " rudimentary " substituents refer to corresponding aliphatic group be straight or branched,
Saturation and containing 1 to 6 carbon atom.
2. a kind of indolone spiral shell thiophane class compound according to claim 1, it is characterised in that in R1What is represented takes
Dai Jizhong, the halogen is fluorine, chlorine or bromine, and the low alkyl group is methyl；In R2In the aromatic ring substituents group of expression, substituted benzene
Ring substitute group is 4- bromophenyls or 3,4- dichlorophenyls.
3. a kind of indolone spiral shell thiophane class compound according to claim 1 or 2, it is characterised in that in R4Represent
Substituted benzene ring substituted radical is in aromatic ring substituents group：4- bromophenyls, 3- bromophenyls, 2- fluorophenyls, 4- aminomethyl phenyls, 4- methoxies
Base phenyl, 2,4 difluorobenzene base orIn R4Heteroaromatic substituted radical is in the aromatic ring substituents group of expression：
4. a kind of indolone spiral shell thiophane class compound according to claim 1, it is characterised in that the R of the compound1、
R2、R3、R4One kind in following combination：
。
5. a kind of preparation method of indolone spiral shell thiophane class compound described in any one of Claims 1 to 4, its feature exists
In reaction equation is as follows：
Wherein, compound of formula VI, Formula VII compound and catalyst VIII are added in solvent, stirred at 20~30 DEG C
10~14h, after reaction completely, continuously adds 10~20min of reaction at pyridine, thionyl chloride, 20~30 DEG C, isolates and purifies, obtain
To target product I；
Wherein, catalyst VIII is thiosemicarbazide bifunctional catalyst.
6. a kind of preparation method of indolone spiral shell thiophane class compound described in claim 5, it is characterised in that catalyst
VIII is in enantiomter or compound A1~A9 any in one kind in compound A1~A9, compound A1~A9
A kind of racemic modification constituted with its enantiomter；Compound A1~A9 structure is as follows：
7. a kind of preparation method of indolone spiral shell thiophane class compound described in claim 6, it is characterised in that
When target product I structure is IA：
Catalyst VIII is A3, A6, A9, A1 enantiomter, A4 enantiomter, A5 enantiomter, A7 pair
Reflect isomers or A8 enantiomter；
When target product I structure is IB：
Catalyst VIII is the enantiomter of A1, A4, A5, A7, A8, A3 enantiomter, A6 enantiomter or A9；
When target product I is racemic modification, catalyst VIII is one kind and its enantiomter group in compound A1~A9
Into racemic modification.
8. the officinal salt of the indolone spiral shell thiophane class compound described in any one of claim 1 to 6.
9. the indolone described in indolone spiral shell thiophane class compound or claim 8 described in any one of claim 1 to 6
Application of the officinal salt of spiral shell thiophane class compound in antineoplastic is prepared.
10. application according to claim 9, it is characterised in that described tumour is lung cancer, intestinal cancer, breast cancer or liver cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710548337.XA CN107235992B (en) | 2017-07-06 | 2017-07-06 | Indolone spiral shell thiophane class compound and its salt, preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710548337.XA CN107235992B (en) | 2017-07-06 | 2017-07-06 | Indolone spiral shell thiophane class compound and its salt, preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107235992A true CN107235992A (en) | 2017-10-10 |
| CN107235992B CN107235992B (en) | 2019-08-20 |
Family
ID=59990869
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710548337.XA Expired - Fee Related CN107235992B (en) | 2017-07-06 | 2017-07-06 | Indolone spiral shell thiophane class compound and its salt, preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107235992B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108409746A (en) * | 2018-05-15 | 2018-08-17 | 中山大学 | A kind of chiral oxo spiro indole class compound and its raceme and preparation method containing pyrroles or indoles and azacycloalkyl structure |
| CN111686798A (en) * | 2020-03-10 | 2020-09-22 | 秦婷 | BINOL axis chiral thiourea organic catalyst for preparing spiro tetrahydrothiophene |
| CN116041366A (en) * | 2022-03-16 | 2023-05-02 | 成都大学 | Chiral 3-spiro-oxindole benzothiophene sulfone derivative, preparation method and application thereof |
| CN116253736A (en) * | 2023-01-06 | 2023-06-13 | 中山大学 | Pyrazole beta-lactam derivative and preparation method and application thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0303418A2 (en) * | 1987-08-11 | 1989-02-15 | Smithkline Beecham Laboratoires Pharmaceutiques | Substituted indolones, useful in the treatment of heart or asthmatic diseases |
| WO2010077839A1 (en) * | 2008-12-15 | 2010-07-08 | Wyeth Llc (Formerly Known As Wyeth) | Substituted oxindol cb2 agonists for pain treatment |
| CN102093370A (en) * | 2011-01-14 | 2011-06-15 | 华南理工大学 | Spirosthydroxyindole heterocyclic compounds and preparation method and use thereof |
| CN102675339A (en) * | 2012-04-27 | 2012-09-19 | 华南理工大学 | Screw epoxidation indole heterocyclic compound as well as synthetic method and purpose thereof |
| CN103992334A (en) * | 2014-05-29 | 2014-08-20 | 中国人民解放军第二军医大学 | Indolone spiral tetrahydrothiopyran antitumour derivatives and preparation method thereof |
| CN106565742A (en) * | 2016-10-24 | 2017-04-19 | 中国人民解放军第四军医大学 | Indolone screw tetralin sulfo-pyran derivative and preparing method and application thereof |
-
2017
- 2017-07-06 CN CN201710548337.XA patent/CN107235992B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0303418A2 (en) * | 1987-08-11 | 1989-02-15 | Smithkline Beecham Laboratoires Pharmaceutiques | Substituted indolones, useful in the treatment of heart or asthmatic diseases |
| WO2010077839A1 (en) * | 2008-12-15 | 2010-07-08 | Wyeth Llc (Formerly Known As Wyeth) | Substituted oxindol cb2 agonists for pain treatment |
| CN102093370A (en) * | 2011-01-14 | 2011-06-15 | 华南理工大学 | Spirosthydroxyindole heterocyclic compounds and preparation method and use thereof |
| CN102675339A (en) * | 2012-04-27 | 2012-09-19 | 华南理工大学 | Screw epoxidation indole heterocyclic compound as well as synthetic method and purpose thereof |
| CN103992334A (en) * | 2014-05-29 | 2014-08-20 | 中国人民解放军第二军医大学 | Indolone spiral tetrahydrothiopyran antitumour derivatives and preparation method thereof |
| CN106565742A (en) * | 2016-10-24 | 2017-04-19 | 中国人民解放军第四军医大学 | Indolone screw tetralin sulfo-pyran derivative and preparing method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| BIAOLIN YIN，等: "Cu(II)-Promoted Transformations of α-Thienylcarbinols into Spirothienooxindoles: Regioselective Halogenation of Dienyl Sulfethers Containing Electron-Rich Aryl Rings", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108409746A (en) * | 2018-05-15 | 2018-08-17 | 中山大学 | A kind of chiral oxo spiro indole class compound and its raceme and preparation method containing pyrroles or indoles and azacycloalkyl structure |
| CN108409746B (en) * | 2018-05-15 | 2021-08-24 | 中山大学 | Chiral oxo spiro indole compound containing pyrrole or indolocarbazacycloalkane structure, racemate thereof and preparation method |
| CN111686798A (en) * | 2020-03-10 | 2020-09-22 | 秦婷 | BINOL axis chiral thiourea organic catalyst for preparing spiro tetrahydrothiophene |
| CN116041366A (en) * | 2022-03-16 | 2023-05-02 | 成都大学 | Chiral 3-spiro-oxindole benzothiophene sulfone derivative, preparation method and application thereof |
| CN116041366B (en) * | 2022-03-16 | 2023-12-22 | 成都大学 | Chiral 3-spiro-oxindole benzothiophene sulfone derivative, preparation method and application thereof |
| CN116253736A (en) * | 2023-01-06 | 2023-06-13 | 中山大学 | Pyrazole beta-lactam derivative and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107235992B (en) | 2019-08-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107235992B (en) | Indolone spiral shell thiophane class compound and its salt, preparation method and application | |
| CN106565742B (en) | Indolone spiral shell tetrahydro thio-pyrylium analog derivative and its preparation method and application | |
| CN103992336B (en) | Oxa-or thia evodiamine anti-tumor derivant and preparation method thereof | |
| CN103992334A (en) | Indolone spiral tetrahydrothiopyran antitumour derivatives and preparation method thereof | |
| Yang et al. | Facile synthesis of spirooxindole-pyrazolines and spirobenzofuranone-pyrazolines and their fungicidal activity | |
| Akaev et al. | 3-(2-Azidoethyl) oxindoles: advanced building blocks for one-pot assembly of spiro [pyrrolidine-3, 3′-oxindoles] | |
| CN106220641B (en) | Containing the indoles volution compound and the preparation method and application thereof for more creating blue hydrocarbon Azulene structure | |
| Yang et al. | Diversity-oriented one-pot multicomponent synthesis of spirooxindole derivatives and their biological evaluation for anticancer activities | |
| WO2007036131A1 (en) | Carzole sulphamide derivatives and their preparation method | |
| Bibian et al. | Multi-gram scale mercury-free synthesis of optically pure 3, 4, 5-trisubstituted 1, 2, 4-triazoles using silver benzoate | |
| Kaur et al. | Synthesis of 1, 4-dihydropyrazolo [4, 3-b] indoles via intramolecular C (sp2)-N bond formation involving nitrene insertion, DFT study and their anticancer assessment | |
| Silvani et al. | Multicomponent access to novel dihydroimidazo [1′, 5′: 1, 2] pyrido [3, 4-b] indol-2-ium salts and indoles by means of Ugi/Bischler–Napieralski/heterocyclization two step strategy | |
| Huang et al. | A facile synthesis of β-amino carbonyl compounds through an aza-Michael addition reaction under solvent-free conditions | |
| Deng et al. | A Formal [3+ 2] Annulation of β‐Oxoamides and 3‐Alkyl‐or 3‐Aryl‐Substituted Prop‐2‐Ynyl Sulfonium Salts: Substrate‐Controlled Chemoselective Synthesis of Substituted γ‐Lactams and Furans | |
| CN107235991B (en) | The raceme and its salt, preparation method and application of indolone spiral shell tetrahydro thio-pyrylium class compound | |
| CN110183373A (en) | A kind of optical activity 1- (hetero) aryl indole derivatives and its preparation method and application | |
| Cao et al. | Facile synthesis of 2-alkynyl oxazoles via a Ce (OTf) 3-catalyzed cascade reaction of alkynyl carboxylic acids with tert-butyl isocyanide | |
| Chen et al. | Enantioselective Michael addition of 3-ethyl carboxylate substituted pyrazolones to 5-alkenyl thiazolones catalyzed by squaramide organocatalyst | |
| Yadav et al. | Microwave assisted base dependent regioselective synthesis of partially reduced chromenes, isochromenes and phenanthrenes | |
| CN107353294A (en) | A kind of method that multi-component reaction of catalysis of iodine prepares indoles volution compound | |
| Teimouri et al. | Uncatalyzed diastereoselective synthesis of alkyliminofurochromone-derived benzylmalononitriles via a three-component cascade reaction: competition between Diels–Alder cycloaddition and Michael addition | |
| Ozeryanskii et al. | ‘Proton sponge’amides: unusual chemistry and conversion into superbasic 6, 7-bis (dimethylamino) perimidines | |
| CN109796471B (en) | Indolone spiro-propane spiro-thiazolone or spiro-tetrahydrothiazolone derivative and preparation method and application thereof | |
| CN108276420B (en) | 8, 13-dihydrobenzo [5,6] chromene [2,3-b ] indole compound and synthetic method thereof | |
| Yang et al. | Synthesis of Luminescent Indolo [2, 1-b] quinazolin-6 (12 H)-ones via a Sequential Ugi/Iodine-Promoted Cyclization/Staudinger/Aza-Wittig Reaction |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20190820 Termination date: 20200706 |